1. Technical Field of the Invention
This invention pertains generally to the identification of sentinel lymph nodes using ultrasonography and, more particularly, to the use of an iron sucrate solution with ultrasonography to identify sentinel lymph nodes.
2. Background of the Invention
The treatment of breast cancer often requires a direct surgical approach to the
tumor within the breast and to the lymph nodes underneath the arm (axilla). The axillary nodes are an important predictor of disease outcome and the information derived from their pathological analysis determines therapeutic alternatives. Those nodes are positive for neoplastic cells in as many as 40% of breast cancers. In the past, the typical approach was to remove as many possible axillary nodes in conjunction with the breast tumor. A morbidity rate of about 20% was associated with this practice. Thus, several methods were developed to identify and biopsy the sentinel lymph node.
The lymph ducts of the breast drain to one lymph node first, the sentinel node, before draining through the rest of the lymph nodes in the axilla. The cellular elements that drain to the lymph or that gain access to lymph nodes are typically the circulating white cells or phagocytes that are involved in the cellular defense mechanism. Although these cells are very large (several tens of micrometers in diameter), they gain access to the lymph space by their ability to deform and migrate through tiny openings. These cells patrol the extracellular space, phagocytose materials, and carry such materials into the lymph and the lymph nodes for further action by the immune system. When cancer occurs in tissues or organs, its loose matrix allows the dislodging of cells that gain access to the lymph space. However, because they lack the functionality of white blood cells, they can become trapped in the lymph node and grow. The first node that traps the cancer is called the sentinel lymph node.
Limiting dissection to the sentinel lymph node can therefore predict the status of the remainder of the nodal system. When the sentinel lymph node is free of neoplastic tumor cells, the remainder of the nodes are negative in nearly 100% of the cases. When the node is found to contain neoplastic cells, it is the only positive node in over 60% of cases and contains five times more micrometastasis than nonsentinel nodes (Hsuch & Giuliano, The Oncologist 1998; 3:165-170). So, in addition to staging, sentinel node resection provides some therapeutic benefit, as all micrometastases are removed in a majority of cases.
Thus, if the sentinel lymph node is free of neoplastic tumor cells, further lymph node biopsies and (further) lymph node dissections can be avoided. The standard of care today allows the surgeon to select patients for axillary dissection only when deemed necessary, a decision based on the information derived from analysis of the sentinel lymph node. In other words, a sentinel lymph node without tumor cells allows the patient to avoid an axillary dissection and the associated morbidity.
Sentinel lymph nodes have been identified by injecting a marking agent into the tumor-bearing tissue and tracing the pathway of the marking agent through the lymphatic system. Visible marking agents such as dyes have been employed to visually detect the sentinel lymph node with the naked eye. Such a method requires significant surgical dissection. Furthermore, the nodes are indistinguishable from the surrounding tissue unless darkly stained and the dyes unfortunately have an unpredictable and rapid clearance rate.
Currently, the sentinel lymph node is routinely identified indirectly, by targeting the signal produced by a radioactive tracer isotope which has been incorporated, for example by phagocytosis, by cells within the lymph node. The radioactive gamma emission signal is picked up with a signal detector (a “gamma probe”). The surgeon then makes an incision in the appropriate location and removes the sentinel lymph node, which is analyzed by the pathologist while the patient is still under anesthesia. If the exam reveals that the sentinel lymph node does have cancer cells, the surgeon proceeds with an axillary dissection at that time. Otherwise, the patient is sent home and awaits the result of the permanent pathologic analysis, which may show cancer cells not seen at the time of surgery. When this is the case, the patient must be returned to the operating room to undergo an axillary dissection. An additional disadvantage of this procedure is that both the patient and medical personnel are exposed to potentially harmful doses of ionizing radiation. Radioactive isotopes also pose environmental contamination and disposal issues.
Attempts have been made to examine the axilla with ultrasonography, a non-invasive imaging technique. While it is sometimes possible to visualize lymph nodes, there is currently no method to clearly identify the sentinel lymph node. If this were possible, a simple needle biopsy could determine if the patient requires further or no additional surgery.
Thus, while the current standard of care for patients diagnosed with breast cancer
includes identification of the sentinel lymph node at the time of surgery, it is still accomplished using both a radioactive tracer substance, such as a gamma ray emitting isotope, and a vital blue dye, such as Isosulfan Blue (Lymphazurin).
The present invention replaces both the radioactive tracer isotope and the vital blue dye with an iron-containing compound, which surprisingly allows positive recognition of the sentinel lymph node by ultrasonographic exam. The procedure of the present invention involves identification of the sentinel lymph node with ultrasonographic equipment using a non-isotopic compound. Once located, the sentinel lymph node may be evaluated for the presence of tumor cells using standard pathologic analysis. There are dramatic advantages to the patient under these circumstances: patients will not receive radioactive material, no general anesthesia or sedation will be needed, incisions might not be necessary, the identification would be done by visualization (in contrast with the currently indirect identification method), and the opportunity to obtain this information prior to the final surgical procedure could avoid the need for the patient to undergo further surgery in certain situations.